Soporific compositions



3,664,958 SOPGREIC CQIVHQSHTKQNS Nathan Millman, Somerville, Ni, assignor to Ortho Pharmaceutical Corporation, a corporation of New Jerse No Drawing. Continuation of application Ser. No. 642,934, Feb. 28, 1957. This application ran. 26, was,

Ser. No. 4,595

17 Claims. (Cl. 167-52) This is a continuation of my copending application Serial No. 642,934, filed February 28, 1957, now abancloned.

This invention relates to soporific compositions that are eifective as hypnotic agents. More specifically, my invention is concerned with compositions containing a known hypnotic, and in addition thereto a Z-aminoalkoxypyrimidine having the formula:

in which R is selected from the group consisting of alkoxy, aryloxy, and arlkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals.

A large number of compounds are well known for their property of inducing sleep or sedation. The barbiturates which are substituted with two organic radicals at the 5-position of the barbituric acid ring system are particularly efiective. Sulfur analogues of the barbiturates are also useful. Compounds having known hypnotic activity vary widely in their molecular structure and functional groups. Thus unsaturated alcohols such as Dormison (3-methyl-1-pentyn-3-ol), the carbamates such as Valmid (l-ethynyl-cyclohexyl carbamate), piperidine derivatives such as Noludar (3,3-diethyl-5- methyl-2,4-piperidinedione), and glyceryl derivatives such as Tolserol (3-ortho-toloxy-1,Z-propanediol) as well as the hydantoins, pyridones, pyrrolidones, and thiazolidones, which share with the 5,5-dialkyl barbituric acids, the structural segment R -R CONH have been employed as hypnotics at various periods.

The synergism of the antipyretic effect of pyrazolone by hypnotics has been reported. Veramon consists of two molecules aminopyrine and one molecule of diethyl barbituric acid. Its antipyretic efiect is greater than the corresponding amount of aminopyrine alone. However, to the best of my knowledge, I am the first to note that the hypnotic effect of the various hypnotics can be potentiated by the addition of certain substituted Z-aminopyrimidines.

It has now been found that compositions containing a hypnotic and a Z-aminoalkoxypyrimidine having the formula:

in which R is selected from the group consisting of alkoxy, aryloxy, and aralkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloXy, and aralkoxy radicals are particularly eifective in inducing sleep and in prolonging the period game Patented May is, 1962.

of sleep induced by the administration of a given amount of drug. The elfect of the composition is greater and more useful than could be anticipated from the known properties of the individual compounds of the type used in preparing the compositions. The utilization of these compositions permits the administration of a considerably reduced amount of a hypnotic with no decrease or even an actual increase in the soporific effect of the drug. This has certain advantages, as the undesirable side eflects of the hypnotics can be considerably reduced.

The compositions of this invention consist of from about 10 parts by weight of a hypnotic together with about parts by weight of the substituted Z-aminopyrimidine to about 250 parts by weight of a hypnotic with about 100 parts by weight of a substituted 2-aminopyrimidine. The relative proportions of the two compounds will naturally vary to some extent according to the particular hypnotic and the particular 2-aminopyrimidine present in the mixture. Of course, mixtures of two or more different hypnotics may be combined with two or more Z-anrinoalkoxypyrimidines, but the relative proportions of the total amount of hypnotic to the total amount of Z-aminoalkoxypyrimidine should be within the limitations described above for maximum potentiation of hypnotic.

Hypnotics which I have noted to be more effective when combined with the Z-aminoalkoxypyrimidines are the barbiturates such as Nembutol (monosodium ethyl [l-methylbutyl] barbiturate), Evipal (N-methylcyclohexenyl barbituric acid), Medomin (S-ethyl S-cyclohepten-l-yl barbituric acid), the unsaturated alcohols such as Dormison (methyl-ethyl-ethynyl carbinol), the carbamates such as Valmid (l-ethynyl-eyclohexyl carbarrrate), the piperidine derivatives such as Noludar (3,3-diethyl- 5-methyl-2,4-piperidinedione) and the glyceryl derivatives such as 3-ortho-toloxy-1,2-propanediol.

The Z-aminoalkoxypyrimidines that I have found to be efliective in increasing the hypnotic activity of the compounds mentioned above are compounds having the formula:

in which R is selected from the group consisting of alkoxy, aryloxy, and. aralkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals. More specifically, the 2-arnino-5-alkoxypyrimidines such as the Z-amino-S- butoxypyrirnidines, the Z-amino-S-hexoxypyrimidine; the 2-amino-S-aryloxypyrirnidines such as the Z-amino-S- benzoxypyrimidine; and the Z-amino-S-aralkoxypyrimidines such as the Z-amino-S-phenethoxypyrimidine are suitable.

The 2-amino-4,5-diall oxypyrimidines were also found to be effective, particularly the 4-methoxy-5-ethoxy, the 4,5'-diethoxy, the 4-butoxy-5-ethoxy, the 4-ethoxy-5-butoxy, and the 4,5-dibutoxy compounds.

Substitution of an aralkoxy or an alkoxy group for the ethoxy groups in the series also synergizes the hypnotic efiect. Examples of such compounds are the 2-amino-4- benzoxy-S-ethoxypyrimidine, the 2-amino-4-phenethoxy-5- ethoxypyrimidine, the Z-amin0-4-ethoxy-S-benzoxypyrimidine, the 2amino-4-ethoxy-5-phenethoxypyrimidine, and the 2-amino-4-benzoxy-5-butoxypyrimidine.

Compounds which are substituted by an alkoxy group in the 6-position on the Z-aminopyrimidine ring also were found to increase the hypnotic effects of known hypnotics. Examples of such pyrimidines are the 2-amino-4-ethoxy-6- ethoxy, and 2-amino-4-ethoxy-S-ethoxy-6-methylethoxy.

The compositions of my invention may be administered by various routes but particularly effective and convenient is the administration of the composition orally. Parenteral administration may also be used for these compositions. The materials may be prepared in any of the usual dosage forms, that is, in the form of capsules, tablets, elixirs, or solutions of various kinds with suitable sweetening and flavoring agents.

The potentiation effect of the substituted Z-amino-pyrimidines on hypnotics may be observed readily on mice or other animals by administering the individual drugs to groups of mice and a combination of the drugs to a third group. The third group showed a definite prolongation and increased depth of sleep over what could be anticipated. Similar etfects may be observed on various other species of animals.

I have measured the hypnotic effect as a function of time (in minutes) during which the animal, when put on its side, can not right itself as it does normally by reflex action. The method is thus generally known as the no righting reflex procedure.

In conducting the tests, the hypnotic time, average minutes value is determined for a certain does of known hypnotic alone, and for a certain dose of the substituted 2-amin0pyrimidine alone. Then both compounds are given at about the same time in their respective doses at which the preceding control tests were conducted. The hypnotic time, average minutes is determined for the combination. The drugs may be given at about the same time, at the same site, or actually mixed before administration. All determinations are conducted on a minimum of four animals and the results are averaged to give the hypnotic time, average minutes. In my animal test experiments, the compositions of this invention are administered to mice by intra-peritoneal injection. I have also administered such compositions to rabbits (intravenous injection), and to rats orally (by stomach tube).

In the tables which follow, the average percent potentiation for the combination of drugs is given as a convenient index of the effectiveness of a particular composition. The

average percent potentiation which appears in the tables is calculated from the formula X =average percent potentiation and 40- 0- 10 3O X 100. X 100-300 Numerous examples of the composition of my invention are summarized in Tables I through IX, inclusive.

Tables I through IV, inclusive, illustrate the effectiveness of combining various 2-aminoalkoxypyrimidines with Nembutal.

Table V illustrates the effectiveness of various hypnotics when combined with 2-arnino-4,5-diethoxypyrimidine.

-Table VI illustrates the effectiveness of various hypnotics when combined with 2-amino-4-benzoxy-5-butoxypyrimidine.

Table VII is significant for its information relative to the intravenous injection of the compositions of my invention.

Table VIII relates to the oral administration of the compositions.

Table IX reports the dose response determinations, or the effective amount in milligrams per kilogram of body weight when the hypnotic is administered together with certain quantities of particular 2-aminopyn'midines.

The sleep-induced animals seem to have no appreciable after effects. The onset of the hypnotic effect is quite rapid. The peak eifect is reached shortly after sleep is induced. No evidence of excitement before sleep is observed.

TABLE I 2-Amin0-5-Alkoxypyrimidines vs. Nembutal, Intraperitoneal Pyrimidlne Nembutal Avg. percent; cpd. alone 40 mgmJkgm. Both cpds. potentiation 100fingmJkgm. hypnos1(sC) hypncsi(sA) ABC X100 ypnosis avg. mm. av mm. avg. min. (B) g B+C 2-amino-5-butoxypyrimldine 0 13. 5 32. 5 141 2-am1 no-5-hexoxypyrimidine 0 13. 0 32. 0 146 2-am1no-5-benzoxypyrlmidine 0 l7. 0 53. 0 212 2-amino-5-phenethoxypyrimidln 0 19. 0 33. 0 74 TABLE II Z-Amino-4,5-Dialkoxypyrimidines vs. Nembutal, Intraperitoneal Pyrimidinc Nembutal Avg. Percent cpd. alone 40 mgmjkgm. Both cpds. potentiation 100 lrngmjlggm. hypn0si(sC) hypnosi(sA) ABC X100 ypn0S1S avg. H1111. avg. min. avg. min (B 3+0 2-amino-4-methoxy-5-ethoxypyrimidine 0 7. 7 54. 8 612 2-amrno-4-e thoxy-5-ethoxypyrimidine 0 20. 0 82. 3 311 2-a1mno-4-but0xy-5-ethoxypyrlmidine. l5. 8 30. 3 72. 3 57 2-amino-4-benzoxy-fi-ethoxypyrimidine O 23. 5 28. 3 20 2-amino-4-phenethoxy-5-ethoxypyrimid 9. 7 31. 0 109. 0 168 2-am no-4-ethoxy-5-butoxypyrimidine 0 7. 7 54. 8 611 2-am1no-4-ethoxy-5-benzoxypyrimidine.. O 31. 7 147. 8 366 2-amino-4-ethoxy-5-phenethoxypyrimidine 19. 5 17. 0 85. 2 128 2-am no-4-benzoxy-5-butoxypyrimidine 0 14. 5 143. 5 889 2 armno-4-butoxy-E-butoxypyrimidine 43. 5 35. O 263. 0 235 TABLE III 2-A min-4,5 Dialkoxypyrimidines vs. Nembutal, Intraperitoneal Pyrimidine Nembutal Afg. Percent cpd. alone 40 mgmJkgm. Both cpds. potentiation 100 mgnL/kgm. hypnosis hypnosis A-B-G X100 hypnosis avg. min. (0) avg. min. (A) avg. min. (B)

2-amino-4-ethoxy-G-ethoxypyrimidine 0 23. 3 33. 8 45 TABLE IV 2-Amfilo-4,5,6 Trialkoxypyrimidines vs. N embutal, Intraperitoneal Pyrimidine N embutai Afg. Percent epd. alone 40 mgnzL/kgm. Both cpds. potentiation IOOmgmJkgm. hypnosis hypnosis AB-O X100 hypnosis avg. min. (0) avg. min. (A) avg. min. (B)

2-amino-4-ethoxy-5-ethoxy-6-methy1-ethoxypyrimidine 14. 27. 5 134. 5 220 TABLE V Z-Amin0-4,5-Dieth0xypyrimidines vs. Various Types of Hypnotics, Intmperitoneal [100 lug/kg. of 2-amino-4,5diethoxypyrimidine in all cases] Py'rimidine Hypnosis 100 mgrn./ Both cpds. Average Hypnotic Dose avg. min. kgm.hypnohypnosis percent mgmJkgm. sis avg. min. potentiation avg. D1111.

1. Barbiturates:

a. Pentobarbital sodium (Nembutal) [monosodium ethyi-(l-methylbutyl) barbiturate] I. 40 20. 0 0 82. 3 312 b. Hexobarbitel (Evipal) [N-methyicyclohexenyl barbit 50 0 0 11.7 no 2. Giyceryl derivatives: a. Mephenesin(To1sero1)[3-ortho-to10xy-L2-p l- 0 0 17.5 m 3. Unsaturated alcohols: 21. Methyiparaiynol (Dormison) [methyl-ethyl-ethynyl carbinol] 200 0 0 77 2 w 4. Piperidine derivatives: a. Methypryion (Noiudar) piperidinedione] 200 24. 0 0 69. 2 188 5. Oycloheptyi derivatives a. Medomin [fi-ethy cycl aci 5O 0 0 22.0 m 6. Cyclohexyl carbamates: a. Ethinamate (V allmd) [l-e mate 100 0 0 17.8 0

TABLE VI 2-Amino-4-Benzoxy-5-Batoxypyrimidines vs. Various Types of Hypnotics, Intraperitoneal Pyrirnidine Both cpds. Dose Hypnosis 50mgm./kgm. hypnosis Average Hypnotic mgmJkgm. avg. min. hypnosis avg. min. percent (0) avg. min. potentiation 1. Barbiturates:

a. Pentobarbital sodium (Nembutal) 14.5 0 143.5 889 b. Hexobarbitai (Evipai) 0 0 24.0 m 2. Cyclohexyi oarbamates:

a. Ethinamate (Vahnid) 0 0 8.0

TABLE VII Alkoxypyrimidines vs. Various Types of Hypnotics, Intravenous Hypnosis Hypnosis Both cpds. Average Hypnotic Dose avg. min. Pyrimidine Dose avg. min. hypnosis percent mgmJkgm. (C) mgmJkgm. (B) avg. min. potentia- A tion 1. Barbiturates:

a. PeDnt'otiarbitaI sodium (Nem- 20 69.5 2-amino-4,5-d.iethoxy pyrimidine 20 0 122.2 76

u a b. Hexobarbitai (Evipai) 15 0 2-arnino-4-benzoxy-5-butoxypyrimi- 10 0 6.0 w

ne. 2. Glyceryi derivatives: a. Me- 50 3.0 2-amino-4,5 diethoxy pyrimidine 20 0 8.5 183 phenesin(To1sero1). r 1

TABLE VIII Alkoxypyrimidines vs. Various Types of Hypnotics, Oral Hypnosis Hypnosis Both opds. Average Hypnotic Dose avg. min. Pyrimidlne Dose avg. min. hypnosis percent mgmJkgm. G mgm/kgm, (B) avg. min. potentia- (A) tlon 1. Barblturates:

a. Peptiliiirbital sodium (N em- 20 2-amlno,-4,5-d.iethoxy pyrimidiue..-. 100 0 27.0 m

40 130. 2 E mino -4 -benzoxy -5 -butoxyprlmi- 100 0 189. 2 37 me. 1). Hexonarbital 100 18 2-am1no-4,5-diethoxy pyrimidine 100 0 5G. 0 331 2. Cyclohexyl oarbamates: a. Eth- 100 0 2-amino-4,5-diethoxy pyrimidine 100 0 38.8 m

inamate (Valtnid).

TABLE IX Dose-Response Determinations Administered Hypnotic Dose range Pyrimidine Dose range mgmJkgm. mgm./kgm.

Intraperitoneal Nernbutal 6O 2-amino-4, fi diethoxypyrimidine 100 D d 40 2-amino-4-benzoxy-5-butoxy-pyrimidinc 50-100 Do 50-100 2-amino-4,5-diethoxypyrimidino 100 Do 50-100 2-amino-4-benzoxy-5-butoxy-pyrim 50 Do" 10- 4O 2-arnino-5,S-diethoxypyrimidine 100 Do 60-200 do 100 Do 40-200 d0 100 Oral 60 do 100 What is claimed is: 1. A soporific composition comprising a Z-amino-pyrimidine having the formula:

are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals; and methyl-ethylethynyl carbinol, the ratio of methyl-ethyl-ethynyl carbinol:2-amino-pyrimidine being from about 102100 to about 250:100 on a parts-by-weight basis.

4. A soporific composition comprising a Z-amino-pyrimidine having the formula:

in which R is selected from the group consisting of lower alkoxy, aryloxy, aralkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals; and l-ethynylcyclohexyl carbamate, the ratio of l-ethynyl-cyclohexyl carbamate:Z-aminopyrimidine being from about 101100 to about 250: 100 on a parts-by-weight basis.

5. A soporific composition comprising a Z-amino-pyrimidine having the formula:

32 t R? p d F; ru-o o-Nui f 11 -0 o-Nr-r,

in which R is selected from the group consisting of lower alkoxy, aryloxy, and aralkoxy radicals and R and R are in which R is selected from the group consisting of lower selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals; and a barbiturate, the ratio of the barbiturate:Z-aminopyrirnidine being from about 10: 100 to about 250:100 on a parts-by-weight basis.

'3. A soporific composition comprising a Z-ainino-pyrimidine having the formula:

alkoxy, aryloxy, and taralkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals; and 3,3-diethyl- 5-methyl-2,4-piperidinedione, the ratio of 3,3-diethyl-5- methyl-2,4-piperidinedione:Z-aminopyrimidine being from about 10:100 to about 250: 100 on a parts-by-weight basis.

6. A soporific composition comprising a Z-amino-py- R (|J rimidine having the formula: R R \III g R -o C-NH 5/ RL-C (ll-NH; 1n which R is selected from the group consisting of lower alkoxy, aryloxy, and aralkoxy radicals and R and R N in which R is selected from the group consisting of lower alkoxy, aryloxy, and aralkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals; and 3-orthotoloxy-l,2-propanediol:Z-aminopyrimidine being from about 100 to about 250: 100 on a parts-by-weight basis.

7. A soporific composition comprising a Z-amino-pyrimidine having the formula:

in which R is selected from the group consisting of lower alkoxy, aryloxy, and aralkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals; and N-methylcyclohexenyl barbituric acid, the ratio of N-methylcyclohexenyl barbituric acidtZ-aminopyridmidine being from about 10: 100 to about 250:100 on a parts-by-weight basis.

9. A soporific composition comprising a Z-aminopyrimidine having the formula:

in which R is selected from the group consisting of lower alkoxy, aryloxy, and aralkoxy radicals and R and R are selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkoxy radicals; .and S-ethyl-S-cyclohepten-l-yl-barbituric acid, the ratio of S-ethyl-S-cycloheptenl-yl-barbituric acid:2-aminopyrimidine being from about 102100 to about 250: on a parts-by-weight basis.

10. A soporific composition comprising about 100 parts by weight of 2-amino-4-methoXy-5-ethoxypyrimidine and from about 10 to about 250 parts by weight of monosodium ethyl (l-methylbutyl) barbiturate.

11. A soporific composition comprising about 100 parts by weight of 2-amino-4-benzoxy-S-butoxypyrimidine and firom about 10 to about 250 parts by Weight of monosodium ethyl (l-methylbutyl) barbiturate.

12. A soporific composition comprising about 100 parts by Weight of 2-amino-4-ethoXy-5-butoxypyrimidine and from about 10 to about 250 parts by Weight of monosodium ethyl (l-methylbu-tyl) barbiturate.

13. A soporific composition comprising about 100 parts by weight of 2-amino-4-benzoxy-S-butoxypyrimidine and from about 10 to about 250 parts by weight of N-methylcyclohexenyl barbituric acid.

14. A soporific composition comprising about 100 parts by weight of 2-amino-4,5-diethoxypyrimidine and from about 10 to about 250 parts by weight of S-ethyl-S-cyclohepten-l-yl-barbituric acid.

15. A soporific composition comprising about 100 parts by weight of 2-amino-4,S-diethoxypyrimidine and from about 10 to about 250 parts by weight of methyl-ethylethylnyl carbinol.

16. A soporific composition comprising about 100 parts by weight of 2-amino-4-benzoxy-S-butoxypyrimidine and from about 10 to about 250 parts by weight of l-ethylnylcyclohexyl carbamate.

'17. A soporific composition comprising about 100 parts by weight of a Z-amino-4,5-diethoxypyrimidine and from about 10 to about 250 parts by weight of monosodium ethyl (l-methylbutyl) barbiturate.

No references cited. 

1. A SOPORIFIC COMPOSITION COMPRISING A 2-AMINO-PYRIMIDINE HAVING THE FORMULA: 